Lung cancer is the leading cause of death from cancer in the United States. Locally advanced or metastatic cancer exists at presentation in 80% of patients; median survival is less than one year. The 5-year survival rates for Stages 3A, 3B and IV non-small cell lung cancer (NSCLC) are about 20%, 8% and 2%, respectively, despite chemotherapy, with or without radiation. NSCLC patients need new therapeutic approaches! CD22 is a membrane glycoprotein adhesion molecule previously thought to be expressed only on B-lymphocytes and non-Hodgkin's lymphoma (NHL). In this proposal, we provide the first strong evidence that CD22 is (surprisingly) also expressed as a surface receptor on lung cancer cells. We propose to study the role of CD22 on lung cancer cells, and to explore CD22-targeting as a new treatment for patients with lung cancer. CD22 is usually thought of as a B-lymphocyte associated glycoprotein adhesion molecule; we have dissected the CD22 signaling cascade at the molecular level. We identified anti-CD22 mAb that bound the two amino-terminal immunoglobulin domains of CD22 and specifically blocked the interaction of CD22 with its ligand. HB22.7 is an anti-CD22 ligand blocking mAb that is highly effective at inducing signal transduction and apoptosis in NHL. HB22.7 has significant efficacy in NHL xenograft models. Based on these data the NCI humanized HB22.7 through the RAID Program and then funded GMP production. Humanized HB22.7 (huHB22.7) could become an exciting new cancer therapy. During studies designed to examine the binding of anti-CD22 constructs to NHL, we serendipitously discovered the expression of CD22 on the majority of our NSCLC cell lines (which had been planned for use as negative controls). Furthermore, HB22.7 targeted NSCLC cells from patient specimens. We initiated NSCLC xenograft trials and HB22.7 demonstrated surprisingly good activity as a naked mAb and as CD22-targeted immunoliposome. Because of substantial new data and the availability of huHB22.7, we hypothesize that HB22.7 will be an effective, non-toxic, new treatment for NSCLC. In order to further develop this exciting new therapy, the following aims are proposed: 1) characterize the breadth of CD22 expression as well as the physiologic and signaling effects of CD22 ligation on NSCLC cells; 2) determine whether CD22 promotes the growth and metastasis of NSCLC cell lines. The potential synergistic effects of HB22.7 with chemotherapeutics known to be useful for therapy of NSCLC will also be assessed; 3) validate and optimize CD22-targeted therapy against NSCLC and metastasis; 4) along with our collaborators, CD22-targeted, cisplatin-containing nanoparticles (NP) will be created. The pharmacokinetics of the NP and their efficacy for treatment of lung cancer will tested in vivo. This work will study the role of CD22 in NSCLC, the potential for CD22-targeted therapy of NSCLC, and will allow for rapid translation of huHB22.7 to patients with NSCLC.